Reversible expression of cardiac MyBP-C using an inducible tet-off system

Abstract

Loss of cMyBP-C has been linked to left ventricular dilation, cardiac hypertrophy and impaired ventricular function in both cMyBP-C constitutive and conditional knockout mice. At present, it remains unclear whether the structural and functional phenotypes associated with the MYBPC3 null mouse are reversible. To test this idea, we generated a cardiac-specific transgenic mouse model using a Tet-Off inducible system to permit the controlled expression of wild-type (WT) cardiac myosin binding protein-C (cMyBP-C) on the MYBPC3 null background. Functional cMyBP-C Tet-off mice were generated by crossing tetracycline transactivator mice with responder mice carrying the WT cMyBP-C transgene. Prior to dietary DOX administration, cMyBP-C expression and left ventricular function in cMyBP-C Tet-off mice were not statistically different from WT mice. Introduction of dietary doxycycline (DOX) for four weeks resulted in a partial knock-down of cMyBP-C expression and commensurate impairment of systolic and diastolic function to levels approaching that observed in MYBPC3 null mice. Subsequent withdrawal of DOX from the diet resulted in the re-expression of cMyBP-C to levels comparable to that observed in WT mice, along with the near complete recovery of in vivo cardiac function. These results indicate that the cardiac phenotypes associated with the MYBPC3 null mouse are reversible, at least in part, and furthermore, validate the use of the Tet-Off inducible system as a means to study the mechanisms underlying hypertrophic cardiomyopathy.